Prenatal dexamethasone exposure (PDE) induces long-term reproductive toxicity in female offspring. We sought to explore the transgenerational inheritance effects of PDE on diminished ovarian reserve (DOR) in female offspring. Dexamethasone was subcutaneously administered into pregnant Wistar rats from gestational day 9 (GD9) to GD20 to obtain fetal and adult offspring of the F1 generation. F1 adult females were mated with normal males to produce the F2 generation, and the F3 generation. The findings showed decrease of serum levels of anti-Müllerian hormone (AMH) that in the PDE group, decrease in number of primordial follicles, and upregulation of miR-17-5p expression before birth in F1 offspring rats. Expression of cyclin-dependent kinase inhibitor 1B (CDKN1B) and Forkhead Box L2 (FOXL2) were downregulated, and binding of FOXL2 and the CDKN1B promoter region was decreased in PDE groups of the F1, F2, and F3 generations. In vitro intervention experiments showed that glucocorticoid receptor (GR) was involved in activity of dexamethasone. These findings indicate that PDE can activate GR in fetal rat ovary and induce DOR of offspring, and its heritability is mediated by the cascade effect of miR-17-5p/FOXL2/CDKN1B. Increase in miR-17-5p expression in oocytes is the potential molecular basis for transgenerational inheritance of PDE effects.

Graphical abstract

中文翻译：

---

卵母细胞中的 MiR-17-5p/FOXL2/CDKN1B 信号编程介导产前地塞米松暴露所致雌性子代大鼠卵巢储备功能下降的跨代遗传

产前地塞米松暴露（PDE）会导致雌性后代出现长期生殖毒性。我们试图探索 PDE 对女性后代卵巢储备​​功能下降 (DOR) 的跨代遗传影响。从妊娠第9天(GD9)至GD20对怀孕Wistar大鼠皮下注射地塞米松，以获得F1代的胎儿和成年后代。F1 成年雌性与正常雄性交配产生 F2 代和 F3 代。研究结果显示，PDE 组的 F1 后代大鼠血清中抗苗勒管激素 (AMH) 水平降低，原始卵泡数量减少，出生前miR -17-5p表达上调。F1、F2 和 F3 代 PDE 组中细胞周期蛋白依赖性激酶抑制剂 1B (CDKN1B) 和 Forkhead Box L2 (FOXL2) 的表达下调，FOXL2 与 CDKN1B 启动子区域的结合减少。体外干预实验表明，糖皮质激素受体（GR）参与地塞米松的活性。这些结果表明，PDE可以激活胎鼠卵巢中的GR并诱导子代的DOR，其遗传力是由miR-17-5p /FOXL2/CDKN1B的级联效应介导的。卵母细胞中miR-17-5p表达的增加是 PDE 效应跨代遗传的潜在分子基础。

图形概要